Predicting cure and hypocalcemia by intraoperative parathyroid hormone decline in normohormonal primary hyperparathyroidism: A multi-institutional validation study.

BACKGROUND: Normohormonal primary hyperparathyroidism is characterized by hypercalcemia and inappropriately normal parathyroid hormone levels. We previously reported that intraoperative parathyroid hormone decline of 50-70% for normohormonal and 75-88% for classic primary hyperparathyroidism during parathyroidectomy was predictive of (1) cure and (2) avoidance of hypocalcemia in a single-institution study (derivation cohort). We sought to externally validate these findings. METHODS: We performed a multi-institutional retrospective cohort study of patients undergoing parathyroidectomy for primary hyperparathyroidism from 2002 to 2019 (validation cohort). Primary outcomes were biochemical cure (calcium <10.3 mg/dL) and postoperative hypocalcemia (≤8.8 mg/dL) ≥6 months postoperatively. Test characteristics of the previously derived thresholds were evaluated in this cohort. RESULTS: A total of 163 (16%) of 1,037 patients had normohormonal primary hyperparathyroidism. Cure rates were similar for normohormonal and classic primary hyperparathyroidism (94% vs 92%, P = .41). In patients who were cured, the median intraoperative parathyroid hormone decrease was lower in normohormonal compared with classic primary hyperparathyroidism (56.8 vs 73.3%, P < .0001). Rates of hypocalcemia were similar for normohormonal and classic primary hyperparathyroidism (14.6% vs 11.9%, P = .44), but increasing percent intraoperative parathyroid hormone decrease beyond 65% disproportionately correlated with hypocalcemia in patients with normohormonal primary hyperparathyroidism. When intraoperative parathyroid hormone thresholds from the derivation cohort were applied, positive predictive values for cure were 97% and 94% for normohormonal and classic primary hyperparathyroidism, respectively; negative predictive values for hypocalcemia were 89% for both groups. For both cohorts combined, a minimal intraoperative parathyroid hormone of 50% provided similar cure rates between groups (95.4% vs 93.8%, P = .42), whereas intraoperative parathyroid hormone exceeding 65% correlated with a greater risk of hypocalcemia in normohormonal compared with classic primary hyperparathyroidism (13.4% vs 6.9%, P = .02). CONCLUSION: This multi-institutional study externally validated that intraoperative parathyroid hormone decrease of 50-65% predicts cure and hypocalcemia in patients with normohormonal primary hyperparathyroidism.

The effects of burst steroid therapy on short-term decongestion in acute heart failure patients with pro-inflammatory activation: a post-hoc analysis of the CORTAHF randomized, open-label, pilot trial.

BACKGROUND: The effect of steroids on congestion in patients with acute heart failure (AHF) is not known. METHODS AND RESULTS: Patients with AHF, NT-proBNP>1500 pg/mL, and high-sensitivity C-reactive protein (hsCRP)>20 mg/L were randomized to once daily oral 40 mg prednisone for 7 days or usual care. In this post-hoc analysis, congestion score was calculated from orthopnea, edema, and rales (0 reflecting lack of congestion, and 9 maximal congestion) at each time point. Among 100 eligible patients randomized, those assigned to prednisone had a greater improvement in congestion score at day 31 (win odds for the prednisone group compared to usual care at day 31 was 1.77 (95% CI 1.17-2.84; p = 0.0066) in all patients and 2.41 (95% CI 1.37- 5.05; p = 0.0016) in patients with IL-6>13 pg/mL at baseline. In patients with congestion score ≥7 at baseline, the effects of prednisone therapy on EQ-5D visual analog scale score were 4.30 (95% CI 0.77-7.83) points at day 7 and 5.40 (0.51-10.29) points at day 31, accompanied by lower heart rate and respiratory rate, and higher oxygen saturation compared to usual care. CONCLUSIONS: In patients with AHF and inflammatory activation, 7-day steroid therapy was associated with reduction in signs of congestion up to day 31. These results need confirmation in larger studies examining potential effects of steroids on congestion, diuresis, fluid redistribution and vascular permeability as well as clinical effects in AHF.

An iron-rich subset of macrophages promotes tumor growth through a Bach1-Ednrb axis.

We define a subset of macrophages in the tumor microenvironment characterized by high intracellular iron and enrichment of heme and iron metabolism genes. These iron-rich tumor-associated macrophages (iTAMs) supported angiogenesis and immunosuppression in the tumor microenvironment and were conserved between mice and humans. iTAMs comprise two additional subsets based on gene expression profile and location-perivascular (pviTAM) and stromal (stiTAM). We identified the endothelin receptor type B (Ednrb) as a specific marker of iTAMs and found myeloid-specific deletion of Ednrb to reduce tumor growth and vascular density. Further studies identified the transcription factor Bach1 as a repressor of the iTAM transcriptional program, including Ednrb expression. Heme is a known inhibitor of Bach1, and, correspondingly, heme exposure induced Ednrb and iTAM signature genes in macrophages. Thus, iTAMs are a distinct macrophage subset regulated by the transcription factor Bach1 and characterized by Ednrb-mediated immunosuppressive and angiogenic functions.

Longitudinal Multiparametric Quantitative MRI Evaluation of Acute and Chronic Multiple Sclerosis Paramagnetic Rim Lesions.

BACKGROUND: Multiple sclerosis (MS) paramagnetic rim lesions (PRLs) are markers of chronic active biology and exhibit complex iron and myelin changes that may complicate quantification when using conventional MRI approaches. PURPOSE: To conduct a multiparametric MRI analysis of PRLs. STUDY TYPE: Retrospective/longitudinal. SUBJECTS: Ninety-five progressive MS subjects with at least one persistent PRL who were enrolled in the CONSONANCE trial. FIELD STRENGTH/SEQUENCE: 3-T/Susceptibility-weighted, T1-weighted, T2-weighted, and fluid-attenuated inversion recovery. ASSESSMENT: Acute/chronic PRLs and non-PRLs were measured at screening, 24, 48, and 96 weeks using quantitative magnetic susceptibility (QS), R2*, and standardized T1w/T2w ratio (sT1w/T2w). PRL analyses were performed for whole lesion, core, and rim. The correlations between PRL core and rim sT1w/T2w, QS, and R2* were assessed. STATISTICAL TESTS: Linear mixed models. A P-value <0.05 was considered significant. RESULTS: There was a significant decrease in sT1w/T2w (-0.24 ± -5.3 × 10-3) and R2* (-3.6 ± 2.2 Hz) but a significant increase in QS (+21 ± 1.3 ppb) using whole-lesion analysis of chronic PRLs compared to non-PRLs at screening. Tissue damage accumulated at the 96-week time point was more evident in acute/chronic PRLs compared to acute/chronic non-PRLs (ΔsT1w/T2w = -0.21/-0.24 ± 0.033/0.0053; ΔR2* = -4.4/-3.6 ± 1.4/2.2 Hz). New, acute PRL sT1w/T2w significantly increased in lesion core (+4.3 × 10-3 ± 1.2 × 10-4) and rim (+5.6 × 10-3 ± 1.2 × 10-4) 24 weeks post lesion inception, suggestive of partial recovery. Chronic PRLs, contrastingly, showed significant decreases in sT1w/T2w over the initial 24 weeks for both core (-2.1 × 10-4 ± 2.0 × 10-5) and rim (-2.4 × 10-4 ± 2.0 × 10-5), indicative of irreversible tissue damage. Significant positive correlations between PRL core and rim sT1w/T2w (R2 = 0.53), R2* (R2 = 0.69) and QS (R2 = 0.52) were observed. DATA CONCLUSION: Multiparametric assessment of PRLs has the potential to be a valuable tool for assessing complex iron and myelin changes in chronic active PRLs of progressive MS patients. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.

Slowly Expanding Lesions Differentiate Pediatric Multiple Sclerosis from Myelin Oligodendrocyte Glycoprotein Antibody Disease.

Slowly expanding lesions (SELs) in adults with multiple sclerosis (MS) indicate a progressive pathological process. Whether SELs are present in pediatric-onset MS (POMS) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is unknown. We studied 19 children with POMS and 14 with MOGAD (median age 14.3 and 9.4 years, respectively) recruited to the Canadian Pediatric Demyelinating Disease Study with: (1) ≥3 research scans 12 months apart; and (2) ≥1 T2-lesions on the earliest scan. A total of 70 SELs from 16 POMS participants and 1 SEL in the MOGAD group were detected. SELs are an early feature of POMS and essentially not a feature of MOGAD. ANN NEUROL 2024.

Pharmacokinetic and Pharmacodynamic Interactions between Food or Herbal Products and Oral Anticoagulants: Evidence Review, Practical Recommendations, and Knowledge Gaps.

Interactions between food and oral anticoagulants (OACs), particularly vitamin K antagonists such as warfarin, are widely recognized and may also be clinically relevant for direct OACs. Pharmacokinetic and pharmacodynamic interactions with food or herbs can lead to anticoagulation potentiation, increased risk of bleeding, or reduced drug efficacy, all compromising patient safety. We conducted a systematic search for randomized controlled trials (RCTs) on PubMed for assessments of interactions between OACs and various ingestants. Since the RCT evidence was slim, we also reviewed prospective longitudinal studies, case series, and case reports to identify possible associations between foods and anticoagulation therapy. We referred to basic or translational studies that shared putative explanations for such interactions, but we failed to identify high-quality evidence in most cases. The limited evidence, small sample size of the studies, conflicting results, and possible heterogeneity in the contents of herbal products prevent a conclusive assessment of these interactions. Existing evidence suggests that (1) cranberry juice consumption (up to 240 mL/d and probably even more) with warfarin is safe; (2) use of green leafy vegetables with a high daily content (more than 250 µg) of vitamin K should be cautioned for patients receiving warfarin, because it may decrease warfarin efficacy. It is also advisable for patients to maintain highly constant intake of green leafy vegetables to ensure stable warfarin effectiveness; (3) ginger, even in small quantities (excluding commercial ginger-flavored beverages, which contain only negligible amounts of ginger), and mango (more than one fruit) can both potentiate warfarin effects; (4) patients taking OACs should avoid St. John's wort due to diminished anticoagulant effect; and (5) consumption of less than 240 mL of grapefruit juice daily is unlikely to interact with OACs. Future longitudinal observational cohort studies and RCTs with larger sample sizes are needed to study specific interactions between food or herbal products and OACs.

Safety and efficacy of evobrutinib in relapsing multiple sclerosis (evolutionRMS1 and evolutionRMS2): two multicentre, randomised, double-blind, active-controlled, phase 3 trials.

BACKGROUND: Evobrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, has shown preliminary efficacy in people with relapsing multiple sclerosis in a phase 2 trial. Here, we aimed to compare the safety and efficacy of evobrutinib with the active comparator teriflunomide in people with relapsing multiple sclerosis. METHODS: EvolutionRMS1 and evolutionRMS2 were two multicentre, randomised, double-blind, double-dummy, active-controlled, phase 3 trials conducted at 701 multiple sclerosis centres and neurology clinics in 52 countries. Adults aged 18-55 years with relapsing multiple sclerosis (Expanded Disability Status Scale [EDSS] score of 0·0-5·5) were included. Participants were randomly assigned (1:1) using a central interactive web response system to receive either evobrutinib (45 mg twice per day with placebo once per day) or teriflunomide (14 mg once per day with placebo twice per day), all taken orally and in an unfasted state, with randomisation stratified by geographical region and baseline EDSS. All study staff and participants were masked to the study interventions. The primary endpoint for each study was annualised relapse rate based on adjudicated qualified relapses up to 156 weeks, assessed in the full analysis set (defined as all randomly assigned participants) with a negative binomial model. These studies are registered with ClinicalTrials.gov (NCT04338022 for evolutionRMS1 and NCT04338061 for evolutionRMS2, both are terminated). FINDINGS: The primary analysis was done using data for 2290 randomly assigned participants collected from June 12, 2020, to Oct 2, 2023. 1124 participants were included in the full analysis set in evolutionRMS1 (560 in the evobrutinib group and 564 in the teriflunomide group) and 1166 in evolutionRMS2 (583 in each group). 751 (66·8%) participants were female and 373 (33·1%) were male in evolutionRMS1, whereas 783 (67·2%) were female and 383 (32·8%) were male in evolutionRMS2. Annualised relapse rate was 0·15 (95% CI 0·12-0·18 with evobrutinib vs 0·14 [0·11-0·18] with teriflunomide (adjusted RR 1·02 [0·75-1·39]; p=0·55) in evolutionRMS1 and 0·11 (0·09-0·13 vs 0·11 [0·09-0·13]; adjusted RR 1·00 [0·74-1·35]; p=0·51) in evolutionRMS2. The pooled proportion of participants with any treatment-emergent adverse event (TEAE) was similar between treatment groups (976 [85·6%] of 1140 with evobrutinib vs 999 [87·2%] of 1146 with teriflunomide). The most frequently reported TEAEs were COVID-19 (223 [19·6%] with evobrutinib vs 223 [19·5%] with teriflunomide), alanine aminotransferase increased (173 [15·2%] vs 204 [17·8%]), aspartate aminotransferase increased (110 [9·6%] vs 131 [11·4%]), and headache (175 [15·4%] vs 176 [15·4%]). Serious TEAE incidence rates were higher with evobrutinib than teriflunomide (86 [7·5%] vs 64 [5·6%]). Liver enzyme elevations at least 5 × upper limit of normal were more common with evobrutinib than with teriflunomide, particularly in the first 12 weeks (55 [5·0%] vs nine [<1%]). Three people who received evobrutinib and one who received teriflunomide met the biochemical definition of Hy's law; all cases resolved after discontinuation of treatment. There were two deaths (one in each group), neither related to study treatment. INTERPRETATION: The efficacy of evobrutinib was not superior to that of teriflunomide. Together, efficacy and liver-related safety findings do not support the use of evobrutinib in people with relapsing multiple sclerosis. FUNDING: Merck.

White matter lipid alterations during aging in the rhesus monkey brain.

The brain of higher organisms, such as nonhuman primates, is particularly rich in lipids, with a gray to white matter ratio of approximately 40 to 60%. White matter primarily consists of lipids, and during normal aging, it undergoes significant degeneration due to myelin pathology, which includes structural abnormalities, like sheath splitting, and local inflammation. Cognitive decline in normal aging, without neurodegenerative diseases, is strongly linked to myelin pathology. Although the exact cause of myelin damage is unclear, older myelin differs from younger myelin, as shown by electron microscopy and altered expression of myelin-related RNAs. However, changes in lipid composition during brain aging remain poorly understood. This study assessed lipid profiles from the frontal lobe corpus callosum, an area where age-related myelin pathology is linked to cognitive decline. Results showed significant changes in lipids with age, revealing distinct age-related profiles. Some lipids that are enriched in myelin sheaths become more saturated, while important structural components, like ceramides, decrease. Disease-associated biomarkers such as cholesterol ester Che (22:6) and sulfatide ST (42:2) also change in older monkeys. Additionally, gene expression of lipid biosynthetic enzymes declines with age, while lipid peroxidation remains stable in the same brain region. This suggests that changes in lipid biosynthesis, rather than oxidative damage, likely account for the differences in lipid composition. Our findings indicate that myelin in the normal aging monkey brain shows diverse lipid changes, which may relate to age-related myelin pathology and could constitute targets for designing nutrient supplements or drugs to rejuvenate the brain's lipidome.

Early overyielding in a mixed deciduous forest is driven by both above- and below ground species-specific acclimation.

BACKGROUND AND AIMS: Mixed forest plantations are increasingly recognised for their role in mitigating the impacts of climate change and enhancing ecosystem resilience. Yet, there remains a significant gap in understanding the early-stage dynamics of species trait diversity and interspecies interactions, particularly in pure deciduous mixtures. This study aims to explore the timing and mechanisms by which trait diversity of deciduous species and competitive interactions influence yield, carbon allocation, and space occupation in mixed forests, both above- and belowground. METHODS: A forest inventory was conducted in planted monocultures, 2-species, and 4-species mixtures of European Acer, Tilia, Carpinus, and Quercus, representing a spectrum from acquisitive to conservative tree species. Competition effects were assessed with linear mixed-effects models at the level of biomass and space acquisition, including leaf, canopy, stem, and fine root traits. KEY RESULTS: Early aboveground growth effects were observed six years post-planting, with significant biomass accumulation after eight years, strongly influenced by species composition. Mixtures, especially with acquisitive species, exhibited aboveground overyielding, 1.5- to 1.9-times higher than monocultures. Fine roots showed substantial overyielding in high diversity stands. Biomass allocation was species-specific and varied markedly by tree size, the level of diversity, and between acquisitive Acer and the more conservative species. No root segregation was found. CONCLUSIONS: Our findings underscore the critical role of species trait diversity in enhancing productivity in mixed deciduous forest plantations. Allometric changes highlight the need to differentiate between (active) acclimations and (passive) tree size-related changes, but illustrate major consequences of competitive interactions for the functional relation between leaves, stem, and roots. This study points towards the significant contributions of both above- and belowground components to overall productivity of planted mixed-species forests.

Aging is associated with reduced inflammatory disease activity independent of disease duration in relapsing multiple sclerosis trial populations.

BACKGROUND: Higher age is associated with less inflammatory disease activity in relapsing-remitting multiple sclerosis (RRMS). It is unknown whether age itself or disease duration underlies this association. OBJECTIVES: This study investigated the effects of age, disease duration, and inflammatory disease activity in people with RRMS. METHODS: Individual patient-level data from five large phase III randomized controlled trials (RCTs) was utilized to investigate the association of both age and disease duration with annualized relapse rate (ARR), contrast-enhancing lesions (CELs), and new T2 lesions on magnetic resonance imaging (MRI) at baseline and follow-up. RESULTS: The data set included 5626 participants. Higher age was associated with lower ARRs, lower CEL number on MRI at baseline and follow-up, and lower new T2 lesion numbers at follow-up. This effect was present in all disease duration groups. For example, we found a lower number of new T2 lesions on MRI during follow-up in higher age groups compared to lower age groups, independent of disease duration. CONCLUSION: Aging in RRMS is associated with a lower risk of inflammatory disease activity, across different disease durations. Age should be taken into account when designing clinical trials and future research should investigate how age should be integrated into personalized predictions of treatment response and risk profiling.

Prognostic factors for worsening and improvement in multiple sclerosis using a multistate model.

BACKGROUND: The long-term disease trajectory of people living with multiple sclerosis (MS) can be improved by initiating efficacious treatment early. More quantitative evidence is needed on factors that affect a patient's risk of disability worsening or possibility of improvement to inform timely treatment decisions. METHODS: We developed a multistate model to quantify the influence of demographic, clinical, and imaging factors on disability worsening and disability improvement simultaneously across the disability spectrum as measured by the Expanded Disability Status Scale (EDSS). We used clinical trial data from the Novartis-Oxford MS database including ~130,000 EDSS assessments from ~8000 patients, spanning all MS phenotypes. RESULTS: Higher brain volume was positively associated with disability improvement at all disability levels (hazard ratio (HR) = 1.09-1.19; 95% credible interval (CI) = 1.02-1.27). Higher T2 lesion volume was negatively associated with disability improvement up to EDSS 6 (HR = 0.80-0.89; 95% CI = 0.75-0.94). Older age, time since first symptoms, and the number of relapses in the past year were confirmed as predictors of future disability worsening. CONCLUSIONS: Brain damage was identified as the most consistent factor limiting the patient's probability for improvements from the earliest stages and across the whole course of MS. Protecting brain integrity early in MS should have greater weight in clinical decision-making.

Tree drought-mortality risk depends more on intrinsic species resistance than on stand species diversity.

Increasing tree diversity is considered a key management option to adapt forests to climate change. However, the effect of species diversity on a forest's ability to cope with extreme drought remains elusive. In this study, we assessed drought tolerance (xylem vulnerability to cavitation) and water stress (water potential), and combined them into a metric of drought-mortality risk (hydraulic safety margin) during extreme 2021 or 2022 summer droughts in five European tree diversity experiments encompassing different biomes. Overall, we found that drought-mortality risk was primarily driven by species identity (56.7% of the total variability), while tree diversity had a much lower effect (8% of the total variability). This result remained valid at the local scale (i.e within experiment) and across the studied European biomes. Tree diversity effect on drought-mortality risk was mediated by changes in water stress intensity, not by changes in xylem vulnerability to cavitation. Significant diversity effects were observed in all experiments, but those effects often varied from positive to negative across mixtures for a given species. Indeed, we found that the composition of the mixtures (i.e., the identities of the species mixed), but not the species richness of the mixture per se, is a driver of tree drought-mortality risk. This calls for a better understanding of the underlying mechanisms before tree diversity can be considered an operational adaption tool to extreme drought. Forest diversification should be considered jointly with management strategies focussed on favouring drought-tolerant species.

High levels of Patient Self Advocacy may confound clinical research in understudied patient populations.

OBJECTIVE: To examine the levels of patient self-advocacy in a sample of participants with Chiari Malformation (CM) and to explore how they relate to clinical outcomes. METHODS: As part of a larger clinical trial addressing chronic pain in patients with CM, 111 participants completed the Patient Self Advocacy Scale (PSAS), the Depression, Anxiety, and Stress Scale (DASS-21), and the Brief Pain Inventory (BPI). RESULTS: PSAS scores indicated a moderately high level of patient self-advocacy (Mean = 3.86 SD = 0.50). The PSAS was not related to depression, anxiety, stress, pain intensity, or pain interference. There were no differences in PSAS according to surgical status (t(61.25) = 0.44, p = 0.66) or use of pain medication (t(109) = 1.05, p = .29). DISCUSSION: Participants in a clinical trial for CM have high levels of pre-existing patient self-advocacy. Research is needed to understand how patient self-advocacy contributes to the management of CM and how it could impact research of individuals with understudied conditions. CLINICAL TRIALS REGISTRATION: NCT05581472.

Burst steroid therapy for acute heart failure: The CORTAHF randomized, open-label, pilot trial.

AIMS: Burst steroid therapy, effective in acute respiratory diseases, may benefit patients with acute heart failure (AHF) in whom inflammatory activation is associated with adverse outcomes. METHODS AND RESULTS: CORTAHF assessed whether burst steroid therapy reduces inflammation and results in better quality of life and clinical outcomes in AHF. Patients with AHF, N-terminal pro-B-type natriuretic peptide >1500 pg/ml, and high-sensitivity C-reactive protein (hsCRP) >20 mg/L were randomized 1:1 to oral, once daily 40 mg prednisone for 7 days or usual care, without blinding. Patients were followed for 90 days. A total of 101 patients were randomized. At day 7 the primary endpoint, hsCRP decreased in both arms - adjusted geometric mean ratios (GMRs) were 0.30 and 0.40 in the prednisone and usual care arms (ratio of GMRs 0.75, 95% confidence interval [CI] 0.56-1.00, p = 0.0498). The 90-day risk of worsening heart failure (HF), HF readmission or death as reported by the unblinded investigators was significantly lower in the prednisone group (10.4%) than in usual care (30.8%) (hazard ratio 0.31, 95% CI 0.11-0.86, p = 0.016). The EQ-5D visual analogue scale score as reported by the unblinded patients increased more in the prednisone group on day 7 (least squares mean difference 2.57, 95% CI 0.12-5.01 points, p = 0.040). All effects were statistically significant in the pre-specified subgroup with centrally-measured interleukin-6 >13 pg/ml. Adverse events, particularly hyperglycaemia, occurred more in the prednisone group with no difference in infection rate. CONCLUSION: In this small open-label study of patients with AHF, burst steroid therapy was associated with reduced inflammation as measured by hsCRP levels at day 7 (primary endpoint). Secondary endpoints showed improved quality of life at day 7 and reduced 90-day risk of death or worsening HF. Large prospective studies are needed to evaluate these findings.

The Pathobiology of Myocardial Recovery and Remission: From Animal Models to Clinical Observations in Heart Failure Patients.

Heart failure with reduced left ventricular (LV) ejection fraction (HFrEF) is a morbid and life-threatening disease, arising secondary to abnormalities of cardiac structure and function that lead to adverse LV remodeling. Implementation of medical and device therapies results in significant improvements in patient outcomes that are associated with reverse LV remodeling and improved LV ejection fraction. This review provides an overview of the pathobiology of reverse LV remodeling in animal models and in HFrEF patients. We emphasize the differences between myocardial recovery and remission as well as the fragile nature of maintaining a state of myocardial remission.

Acute Ketone Monoester Supplementation Does Not Change Exercise Efficiency during Incremental Cycling in Trained Individuals.

METHODS: 28 adults (16 males and 12 females) aged 30 ± 10 y [peak oxygen uptake (V̇O2peak): 59 ± 11 ml·kg-1·min-1] completed three experimental trials in a randomized, crossover, and double-blinded manner. Participants ingested either 0.3 (KE-LO) or 0.6 (KE-HI) g·kg-1 body mass of KE or a flavour-matched placebo (PLAC) ~30 min prior to exercise. Exercise involved a 3-minute warm-up, three 5-minute stages at fixed incremental workloads corresponding to 75%, 100%, and 125% of individual ventilatory threshold, followed by a ramp protocol to volitional exhaustion to determine peak power output (PPO). RESULTS: Venous blood [ß-hydroxybutyrate], the major circulating ketone body, was higher after KE ingestion compared to PLAC (KE-HI: 3.0 ± 1.1 ≥ KE-LO: 2.3 ± 0.6 ≥ PLAC: 0.2 ± 0.1 mM; all p ≤ 0.001. There were no differences between conditions in the primary outcome exercise economy, nor gross efficiency or delta efficiency, when analyzed over the entire submaximal exercise period or by stage. Heart rate and ventilation were higher in KE-HI and KE-LO compared to PLAC when assessed over the entire submaximal exercise period and by stage (all p ≤ 0.05). PPO after the ramp was lower in KE-HI compared to both KE-LO and PLAC (329 ± 60 vs 339 ± 62 and 341 ± 61 W respectively; both p < 0.05) despite no difference in V̇O2peak. CONCLUSIONS: KE ingestion did not change indices of exercise efficiency but increased markers of cardiorespiratory stress during submaximal incremental cycling and reduced PPO.